Genetic Variant TPPP2:p.Arg133Leu (chr14-21031962-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_173846.5(TPPP2):c.398G>T(p.Arg133Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,990 control chromosomes in the GnomAD database, including 16,915 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.11 ( 1293 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15622 hom. )

Consequence

TPPP2
NM_173846.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.15

Variant links:

Genes affected

TPPP2 (HGNC:19293): (tubulin polymerization promoting protein family member 2) Enables tubulin binding activity. Involved in regulation of flagellated sperm motility. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TPPP2 links:

NDRG2 (HGNC:14460): (NDRG family member 2) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that may play a role in neurite outgrowth. This gene may be involved in glioblastoma carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

NDRG2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031427443).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPPP2	NM_173846.5 link	c.398G>T	p.Arg133Leu	missense_variant	Exon 4 of 4	ENST00000321760.11	NP_776245.2	P59282

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPPP2	ENST00000321760.11 link	c.398G>T	p.Arg133Leu	missense_variant	Exon 4 of 4	1	NM_173846.5	ENSP00000317595.6		P59282

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17308

AN:

152048

Hom.:

1291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0409

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.0986

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.0786

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.119

GnomAD3 exomes

AF:

0.152

AC:

38245

AN:

251416

Hom.:

3540

AF XY:

0.153

AC XY:

20739

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0383

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.290

Gnomad SAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.0753

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

AF:

0.139

AC:

202848

AN:

1461824

Hom.:

15622

Cov.:

AF XY:

0.140

AC XY:

101810

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0362

Gnomad4 AMR exome

AF:

0.232

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.283

Gnomad4 SAS exome

AF:

0.181

Gnomad4 FIN exome

AF:

0.0779

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.114

AC:

17306

AN:

152166

Hom.:

1293

Cov.:

AF XY:

0.116

AC XY:

8596

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0409

Gnomad4 AMR

AF:

0.187

Gnomad4 ASJ

AF:

0.0986

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.181

Gnomad4 FIN

AF:

0.0786

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.131

Hom.:

3297

Bravo

AF:

0.119

TwinsUK

AF:

0.130

AC:

483

ALSPAC

AF:

0.140

AC:

539

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.127

AC:

1088

ExAC

AF:

0.148

AC:

18021

EpiCase

AF:

0.126

EpiControl

AF:

0.125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.38

MPC

0.20

ClinPred

0.038

GERP RS

3.6

Varity_R

0.61

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over